Inherited retinal diseases are a large group of genetically heterogeneous disorders, that when considered as a whole are the leading cause of blindness in the world. These diseases range to include disorders such as retinitis pigmentosa (RP) which affects one in every 1000 individuals, and macular degeneration, which affects 1 in 3 individuals over the age of 65. It is clear that the severity of disease is strongly influenced by genetic factors. Our long-term goal is to understand the transcriptional networks regulating photoreceptor generation and maintenance, in order to identify novel targets that may be amenable for improved treatment strategies for retinal disease. The PI was the first to report that mutations in human Nr2e3 cause the recessive ESCS, and mutations in mouse Nr2e3 cause excess production of blue opsin expressing cone cells with progressive retinal degeneration. Our previous studies and the work of others demonstrate a crucial role for the nuclear receptor Nr2e3 in multiple transcriptional networks to regulate the retinal development and function. Patients with Nr2e3 mutations show significant variability in severity of the disease phenotype. These phenotypic disparities underscore the significance of human modifier genes influencing retinal diseases. We hypothesize that Nr2e3 and its cofactor Nr1d1 are master regulators able to modulate the network of genes that influence retinal disease in many IRDs and thereby serve as potent modifiers of retinal degeneration. The goals of this study are to determine the efficacy and capacity of nuclear the receptors Nr2e3 and Nr1d1 in rescuing multiple forms of retinal disease. We will accomplish these goals using modern molecular genetic and genomic approaches. Specifically we will 1) determine the broad-spectrum efficacy of Nr2e3 and Nr1d1 to ameliorate photoreceptor degeneration in five distinct retinal degeneration models; and 2) develop an effective preclinical gene delivery method for Nr2e3 and Nr1d1; and 3) determine the mechanism by which Nr2e3 and Nr1d1 rescue retinal disease in multiple models of photoreceptor degeneration. Preliminary studies show that Nr2e3 and Nr1d1 can rescue two disparate models of retinal disease. These preclinical studies will provide valuable insight leading to clinical studies and the development of viable therapeutics to attenuate or prevent retinal degeneration.